代谢性心血管疾病早期内皮细胞损伤预警与干预研究：循环miR-24靶向调控TRPM4通路

Endothelial injury, a major initiating step in the process of atherosclerosis, is thought to be a key event in the development and progression of severe cardiovascular diseases, which can result from and/or contribute to several disease processes, as occurs in diabetes mellitus, hypercholesterolemia and hypertension. Vascular endothelial cells are early and primary targets of hyperglycemia, hypercholesterolaemia and salt-sensitive hypertension damage in cardiometabolic disease. However, the common regulators of endothelial injury in these metabolism disorders have not been elucidated yet. MicroRNAs (miRNAs) have been recently detected in the circulation of patients with cancer, diabetes and cardiovascular disease, where they are associated with specific clinical parameters. Circulating microRNAs have been proposed as possible molecular markers of several diseases. Previous investigations have revealed that microvesicles and High-Density Lipoproteins (HDL) can transfer miRNAs from donor cells to recipient cells with functional gene regulatory consequences. Our previous study had shown the correlation of low expression of circulating miR-24 in plasma and vascular endothelial cells with disorders like salt-sensitive hypertension, high-fat diet obesity and type 2 diabetes mellitus. Bioinformatics analyses found out that transient receptor potential cation channel subfamily M member 4 (TRPM4) is a major miR-24 target and is associated with the early stage of endothelial injury. TRPM4 is a Ca2+-activated nonselective cation channel and is permeable to Na+ mediating cell membrane depolarization, In this study, we will prove that decreased circulating miR-24 is closely related to endothelial dysfunction, and illuminate that circulating miR-24 is a possible early warning signal of endothelial injury in metabolism disorders. Our project hypothesize that down-regulation of circulating miR-24 may lead to endothelial injury by upregulating TRPM4, which can induce endothelial Na+ overload. Unrestricted influx of Na+ could promote water entry resulting in cell swelling, loss of cell shape, cell detachment, plasma membrane disintegration, and finally oncotic cell death. Moreover, overexpression of miR-24 or inhibition of TRPM4 can significantly rescue the endothelial functions and produce a protective effect against the cell injury induced by high levels of circulating sodium, glucose or lipids. Therefore, this study will extend the characterization of miR-24/TRPM4 regulatory pathway as a new endogenous protective mechanism of vascular endothelial injury, provide a new target and intervention strategy for the prevention and treatment of cardiometabolic disease.

内皮损伤为众多重大心血管疾病发生的关键环节，高糖、高血脂、高盐等代谢性因素均可导致血管内皮细胞损伤，其共同的调节分子和针对性的早期干预措施尚属空白。本研究将证明循环miR-24在高糖、高脂、高盐等代谢紊乱时表达均下降，与内皮功能受损密切相关，并可作为早期内皮损伤共同的预警因子；揭示TRPM4一种可通透钠离子的非选择性阳离子通道为miR-24的作用靶点，早期循环/内皮中miR-24的下降导致TRPM4通道过度开放，内皮细胞钠离子内流增多并伴有水分子进入导致内皮细胞肿胀；通过补充外源性miR-24分子，特异性干预miR-24/TRPM4代谢性内皮细胞损伤的共同调节环节，将成为修复早期血管内皮损伤的有效手段。本课题将揭示循环miR-24为代谢综合征内皮细胞早期损伤的共同预警因子，且miR-24/TRPM4为一个新的血管内皮损伤内源性保护机制，拓展了对重大心血管疾病内皮损伤理论和干预手段的新认识。

内皮损伤是心血管疾病发生的初始环节，寻找新的调控靶点及防治药物具有重大科学意义,其是否具有共同的调节分子尚未可知。TRPM4作为一种非选择性阳离子通道，在多种血管组织内皮中表达，已有研究证实其参与病理状态下血管内皮功能的调节，本项目主要开展TRPM4参与内皮损伤的作用及机制研究。研究结果如下：（1）TRPM4主要在血管内皮细胞质膜上表达，在盐敏感高血压大鼠内皮细胞中表达增高，且培养的人脐静脉内皮细胞在过氧化氢、醛固酮、三氧化二砷等损伤因素处理后，TRPM4表达上调。（2）经上述损伤因素作用后，血管内皮细胞活力下降，细胞凋亡增加，细胞迁移能力改变，且黏附分子增加，同时给予TRPM4阻断剂9-菲酚或TRPM4特异siRNA可明显改善上述指标。（3）经上述损伤因素作用后，血管内皮细胞内钠、钙超载，ROS聚集，在给予9-菲酚或siRNA后上述指标明显改善，说明过氧化氢、醛固酮、三氧化二砷等损伤机制可能是通过促进TRPM4表达，增加钠钙超载，激活氧化应激加重内皮损伤。通过本项目的研究，我们发现了TRPM4有可能是过氧化氢、醛固酮、三氧化二砷等多种损伤因素造成血管内皮损伤的共同调节环节，抑制TRPM4活性或降低其表达将成为早期血管内皮保护的有效手段。本课题揭示抑制TRPM4功能可成为一个新的血管内皮损伤内源性保护机制，本研究对心血管疾病内皮损伤理论和干预手段提供了新认识。

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